Multiple families of signaling molecules, including BMP, FGF, Shh, and Wnt protein, have been implicated in mediating tissue interactions that govern tooth development. Despite significant progresses in the last two decades since BMP4 was identified as a potential morphogen in during tooth initiation, functional mechanisms of these signaling pathways and how they act coordinately to regulate tooth formation remain elusive. Our long-term goal to delineate the molecular mechanisms underlying odontogenesis, which shall shed light on for better understanding of genetic related dental abnormalities and tooth regeneration in humans. Based on our previous and preliminary studies, we hypothesize that BMP and Wnt signaling pathways exert distinct but synergistic functions in controlling dental epithelium development, with Wnt/b- catenin signaling regulating odontogenic fate and BMP-mediated non-canonical signaling regulating cell proliferation, while Smad4-independent canonical BMP signaling (named as atypical canonical BMP signaling) acting in the dental mesenchyme to control odontogenic program by regulating Msx1 expression. Two aims are proposed to test this hypothesis. In Aim 1, we will several unique transgenic/knockout mouse lines dissect distinct and synergistic biological functions of Wnt- and BMP-mediated signaling pathways in the regulation of early tooth development. In this aim, we will: (1) Establish a novel function for Noggin as a Wnt signaling antagonist; (2) Establish BMP signaling as a major regulator for cell proliferation but not for odontogenic fate in the dental epithelium; (3) Define synergistic function of BMP and Wnt signaling in early tooth development; (4) Establish definite signaling function for ?-catenin in tooth development. In Aim 2, we will use several transgenic/knockout mouse line combined with cell culture, biochemistry, and molecular biology approaches to investigate the role and regulation of atypical canonical BMP signaling in the dental mesenchyme. In this aim, we will; (1) Establish that TGFb signaling is primarily responsible for Smad1/5/8 activation in the dental epithelium; (2) Determine functional operation of atypical canonical BMP signaling in the dental mesenchyme; and (3) Investigate regulatory mechanism of atypical canonical BMP signaling in the dental mesenchyme. Results from these proposed studies will greatly enhance our understanding of functional mechanisms of BMP and Wnt signaling in tooth development and challenge the current model of the canonical BMP signaling.